February 7, 2009

The Athlete's gene: ACTN3

Every year in the Olimpic Games more and more marks are broken for awesome athletes. Every day we read at the newspapershow much money earned an elite’s athlete. That is the image that our children see like an inspiration for their future lives and some parents use these fantasies to force their children to follow the hard live of a professional sportiest. Whatever motivation always we search to way to increase our capacities and newly genetics play a fundamental role with the ACTN 3 gene.

ACTN3 actinin, alpha 3 [Homo sapiens] Alpha-actinin is an actin-binding protein with multiple roles in different cell types; it is located in chromosome 11q13.1.

The ACTN3 gene encodes the protein α-actinin-3. α-Actinin-3 isan actin-binding protein that is structurally related to dystrophin. Alpha-actinin is a cytoskeletal actin-binding protein and a member of the spectrin superfamily, which comprises spectrin, dystrophin and their homologues and isoforms. It forms an anti-parallel rod-shaped dimer with one actin-binding domain at each end of the rod and bundles actin filaments in multiple cell-type and cytoskeleton frameworks. In non-muscle cells, alpha-actinin is found along the actin filaments and in adhesion sites. In striated, cardiac and smooth muscle cells, it is localized at the Z-disk and analogous dense bodies, where it forms a lattice-like structure and stabilizes the muscle contractile apparatus. Besides binding to actin filaments alpha-actinin associates with a number of cytoskeletal and signaling molecules, cytoplasmic domains of transmembrane receptors and ion channels, rendering it important structural and regulatory roles in cytoskeleton organization and muscle contraction.

In humans, two genes encode for skeletal muscle α -actinins:ACTN2, which is expressed in all skeletal muscle fibers, vs.ACTN3, whose expression is limited to fast-twitch muscle fibers(100% of type IIb/x fibers and 50% of type IIa fibers). α-Actinins are important structural components of theZ-membrane where they form the crosslink between the thinactin filaments. They have a static function in maintainingordered myofibrillar arrays and a regulatory function in coordinatingmyofiber contraction).

Alpha-actinins are structural proteins of the Z-line. Human skeletal muscle expresses two alpha-actinin isoforms, alpha-actinin-2 and alpha-actinin-3, encoded by their respective genes ACTN2 and ACTN3. ACTN2 is expressed in all muscle fiber types while only type II fibers, and particularly the type IIb fibers, express ACTN3.

ACTN3 (R577X) polymorphism results in loss of alpha-actinin-3 and has been suggested to influence skeletal muscle function. The X-allele is less common in elite sprint and power athletes, than in the general population, and has been suggested to be detrimental for performance requiring high power.

α-Actinins interact with themselves, structural proteins of thecontractile machinery, metabolic enzymes, and signaling proteins, among them are also members of the Z-linelocalized calsarcin family. These bind to calcineurin, aCa2+- and calmodulin-dependent protein phosphatase, which isa signaling protein and is hypothesized to play a role in thedetermination of muscle fiber type and muscle hypertrophy,although it does not seem to be implicated in muscle fiber growthin regenerating muscle.

Based on genetic epidemiological studies, about half of thevariability in fiber type distribution in human muscles is determinedby genetic factors. Through its interaction with calcineurin,polymorphisms in the ACTN3 gene could conceivably contributeto heritability of fiber type distribution. The force-generatingcapacity of type II muscle fibers at high velocity, the speedof movements, and the capacity to adapt to training are allstrongly genetically influenced. The contribution of geneticfactors in strength measures in part varies according to theangle, to the contraction type, and to some extent the contractionvelocity. Contractile property differences according tothe presence/absence of α-actinin-3 in sarcomeres of fast-typemuscle fibers might also contribute to individual differencesin power output.

A common variant of the ACTN3 gene, R577X, results in complete deficiency of the alpha-actinin-3 protein in the fast skeletal muscle fibers of more than a billion humans worldwide. Scientific studies involving elite level athletes suggest that the presence of this specific muscle protein contributes to the muscle's ability to generate forceful contractions at high velocity. Depending on ethnicity, 20 to 50 per cent of people have a variant of the gene R577X, which prevents the ACTN3 gene from producing the muscle protein. Generally, African-Americans have the lowest incidence of the mutation, while Asians have the highest.

This gene is one measure of natural-born athletic ability. Other studies have shown that athletes having the variant in both copies of the ACTN3 gene may have a natural predisposition for endurance, such as distance running, distance swimming and cross-country skiing. Athletes having the variant in one copy of their ACTN3 gene may be equally suited for sports requiring both endurance and sprint / power characteristics such as basketball, tennis, volleyball and cycling.

Athletes that do not carry this variant in either copy of the ACTN3 gene may have a natural predisposition for speed / power sports such as football, weight lifting and sprint events.

The alpha-actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. Alpha-actinin-3 is the most-highly specialised of the four mammalian alpha-actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion (approximately 18%) of the human population is totally deficient in alpha-actinin-3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent works have revealed a strong association between R577X genotype and performance in a variety of athletic endeavours. Several authors are currently exploring the function and evolutionary history of the ACTN3 gene and other alpha-actinin family members. The alpha-actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution. On the other hand, knowing this information may be helpful, not in eliminating choices for sport activities but adding exposure to a host of team or individual sport events that may come easier to a young athlete.

Well, this is the landscape. What do you think? I guess that we need to make the next reflections:

What happens if you have the mutation and you really wish to be an athlete? This is not a real limitation, the success in the sports depend of several variables like training, support, desire, effort, money and it needs to add a very important random factor like the good luck.

What about if you don’t have any mutation? Are you a complete athlete? Well, no. It’s clear that all will depend of the same factors that I showed before.

Is this a necessary genetic test? No, like all the genetic test is up to you. Even if you are young and want to decide about your choices in your future, is this a test only for fun for now. If you are a veteran professional sportiest believe you don’t want to know anything about your genetic condition.

What about the future? It will be very interesting, probably we’ll see more specific test in this field related to specific sports.

It remains a lot of aspects to discuss in this theme. The following is a list of ACTN3 gene research articles that likely are interesting for you:

North K. (2008) Why is alpha-actinin-3 deficiency so common in the general population? The evolution of athletic performance. Twin Research in Human Genetics. 11:384-394.

Druzhevskaya et al. (2008) Association of the ACTN3 R577X polymorphism with power athlete status in Russians, European Journal of Applied Physiology 103:631–634